Date of Award
8-31-2026
Document Type
Open Access Thesis
Degree Name
Master of Science (MS)
Department
Biology
First Advisor
Kai Zou
Abstract
Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder characterized by muscle weakness, degeneration, fibrosis, and impaired muscle regeneration. Mitochondrial dysfunction is an early pathological feature of DMD and has been linked to excessive mitochondrial fission. Dynamin-related protein 1 (Drp1) is a central regulator of mitochondrial fission, a key process in regulating mitochondrial quality and function. Inhibition of Drp1-mediated mitochondrial fission has shown promise as a potential therapeutic target for alleviating pathology and dysfunction in dystrophic muscle. The objective of this study was to determine whether partial skeletal muscle-specific ablation of Drp1 could improve muscle pathology and mitochondrial health in a mouse model of DMD.
Methods: Male D2-mdx mice with tamoxifen- inducible skeletal muscle-specific partial Drp1 ablation (mdx-Drp1+/-) and mdx controls received tamoxifen injections (75 μg/g body weight, intraperitoneal) for 5 consecutive days. Muscle function (grip strength and hangwire tests) was assessed longitudinally for up to 14 weeks post-tamoxifen injection. At 19 weeks post-tamoxifen injection, tissues were collected for histological, molecular, and mitochondrial analyses, including measurements of mitochondrial respiration and hydrogen peroxide production in isolated quadriceps mitochondria. In addition, molecular markers associated with mitochondrial dynamics, oxidative stress, inflammation, fibrosis, and regeneration were assessed (n=8/group). Muscle function was analyzed using grip strength and hangwire testing and histological analyses were performed using hematoxylin and eosin and Masson's trichrome staining. Mitochondrial respiration and hydrogen peroxide production ( were measured in isolated mitochondria from the quadriceps (quad), while gene and protein expression of molecular markers were assessed by quantitative PCR (qPCR) and immunoblotting.
Results: Partial skeletal muscle-specific Drp1 ablation improved skeletal muscle performance, with mdx-Drp1+/- mice exhibiting greater hangwire impulse at 9 weeks post tamoxifen injection (P = 0.0002) and greater grip strength normalized to body weight at 6 weeks (P = 0.01) compared with mdx controls. In addition, histological analysis demonstrated reduced fibrosis (P = 0.005) and a trend toward larger muscle fiber size (P = 0.07) in mdx-Drp1+/- mice in comparison to the mdx control mice. Molecular analyses confirmed that partial ablation of skeletal muscle Drp1 resulted in lower expression of the mitochondrial fission adaptor protein mitochondrial fission factor (MFF; P = 0.01), while most other markers of mitochondrial dynamics, mitophagy, and mitochondrial biogenesis were unchanged. Basal mitochondrial respiration was higher in mdx-Drp1+/- mice (P = 0.003), whereas mitochondrial hydrogen peroxide production did not differ between groups. Importantly, there were trends toward greater gene expression of antioxidant regulators NRF2 (P = 0.07) and GPX4 (P = 0.06) in mdx- Drp1+/- mice when compared to mdx control mice.
Conclusion: These findings demonstrate that partial skeletal muscle-specific ablation of Drp1 improves muscle quality and function, as well as histological fibrosis in dystrophic muscle via mitochondrial fissioning. The results support a critical role for skeletal muscle Drp1-mediated mitochondrial fission in the progression of DMD pathology and suggest that alterations to mitochondrial dynamics may represent a therapeutic strategy for treating DMD.
Recommended Citation
Duzz, Tessa L., "Effect of Partial Ablation of Skeletal Dynamin Related Protein 1 on Mitochondrial Health, Inflammation, and Fibrosis in a Mouse Model of Duchenne Muscular Dystrophy" (2026). Graduate Masters Theses. 984.
https://scholarworks.umb.edu/masters_theses/984
Included in
Animal Experimentation and Research Commons, Cell Biology Commons, Cellular and Molecular Physiology Commons, Genetics Commons, Laboratory and Basic Science Research Commons, Musculoskeletal Diseases Commons
Comments
Free and open access to this work is made available to the UMass Boston community by ScholarWorks at UMass Boston. Those not on campus and those without a UMass Boston campus username and password may gain access to this work through Interlibrary Loan. If you have a UMass Boston campus username and password and would like to download this work from off-campus, click on the “Off-Campus Users” button.